Epithelial Component Research Articles

A Probing of the Issue of Detecting IgG, IgG4 and IgA Antibodies to Laminin 332 Epitopes in Mucous Membrane Pemphigoid: A Clinical-Laboratory Experience of a Single Central European University Dermatology Department.

PurposeMucous membrane pemphigoid (MMP) is a very rare autoimmune bullous disease, affecting predominantly the mucosae and characterized by autoantibodies to the epithelial basement membrane components. Laminin 332 (Ln-332) is one of the most probable antigens with association with malignancy. The laboratory diagnosis of Ln-332-mediated autoimmunity is troublesome. The aim here was to comparatively examine IgG, IgG4, and IgA autoantibodies specific to α3, β3 or γ2 subunits of Ln-322 in MMP patients using the BIOCHIP mosaic-based indirect immunofluorescence technique (IIF).Patients and MethodsSera from 15 MMP patients were studied. BIOCHIP mosaic-based Ln-332 IIF, direct immunofluorescence, ELISA tests for anti-BP180/BP20 IgG antibodies and statistical analyses were performed.ResultsOf all the 15 sera examined for IgG4 antibodies, only 1 (6.67%) reacted with the α3 chain, 0 with the β3 chain, and 0 with the γ2 chain. No positive reactivity was seen with the IgG and IgA antibodies. BIOCHIP mosaic-based IIF with Ln-332 showed 100% sensitivity, 8% specificity, 21% positive predictive value, and 100% negative predictive value in relation to the diagnostic gold standard of DIF. The concomitant malignancies were revealed in three cases.ConclusionThe detection of antibodies to Ln-332 chains is occasional in Polish MMP sufferers. Still, the evaluation of IgG4 antibodies in MMP can reduce the false-negative results.

Mullerian Adenosarcoma of Uterus and Cervix- A Report of Four Cases with Review of Literature

Uterine sarcomas are rare female genital tract malignancies. Mullerian adenosarcoma is a rare biphasic malignant mesenchymal tumor comprising of a benign glandular and malignant (usually low grade) stromal component, both of which are integral and neoplastic constituents of the tumor.[1] This tumor represents less than 8% of uterine sarcomas. About 200 cases have been reported in the literature so far [2] of which 22 case were from India. Adenosarcomas are usually low grade. Sarcomatous overgrowth is defined as the presence of sarcomatous component is more than 25% of the tumor volume. High grade morphology was termed adenosarcoma with sarcomatous overgrowth (i.e, presence of pure sarcoma , without epithelial component comprising 25% of the tumor).The features of high grade sarcomatous overgrowth include severe nuclear pleomorphism, prominent nucleoli , increased mitotic activity and necrosis[2]. Herein, we present four cases of adenosarcoma of the uterine corpus and cervix, discuss their clinico-pathological findings in detail and add a note on the recent and evolving concepts

Early Recurrence of Cromophobic Renal Cell Carcinoma with Sarcomatoid and Rhabdoid Differentiation: About a Case

Chromophobic renal cell carcinoma with sarcomatoid differentiation is a rare tumor characterized by a biphasic tumor with both classic epithelial components and sarcomatoid components with poor prognostic factors, usually in association with the rhabdoid contingent which has the potential to behave aggressively and metastasize. We report a particular case of recurrence of this entity in a male patient in which the diagnosis was suspicious preoperatively for the tumor evolution time and the size of the mass and the imaging data performed. The patient underwent extensive left total nephrectomy and lymph node dissection. The postoperative follow up was marked by early appearance of recurrence within 6 weeks after surgery.

A Modern View of Morphological Changes in the Gums in the Course of Inflammatory Processes

The purpose of the study was the analysis of literature sources with the study of a modern view of morphological changes in the gums in the course of inflammatory processes. Materials and methods. Review and analysis of scientific and medical literature based on databases such as Scopus, Web of Science, MedLine, PubMed, NCBI, the study of which does not exceed 10 years, including literature reviews and clinical trial results. Results and discussion. The analysis of the literature indicates significant morphological changes in the gums in the course of chronic catarrhal gingivitis, which occurs in both the epithelium and their own plate. Thus, the epithelium responds with signs of keratinization disorders. In the course of inflammatory processes in gums, changes of the morphological organization both in epithelial and connective tissue component have been observed. The cytoplasm of the cells of the spiny layer contains granularity, the nuclei are pyknotic and hyperchromic, the boundaries between the cells lose clarity. There is a sharp increase in the amount of glycogen in the cells of the spiny layer. Connective tissue undergoes changes in the form of disorganization, which manifests itself in focal or diffuse gamma metachromasia. The focus of inflammation is clearly separated from the surrounding connective tissue by fibrous bands, which is accompanied by the accumulation of PAS-positive substances and glycosaminoglycans. Changes in the microcirculatory tract of the gums are manifested by dilation of capillaries, venules with diapedetic hemorrhages, endothelial proliferation, swelling of the basement membrane, and the appearance of pericellular oedema. There is moderate fibrosis of the own plate of a mucous membrane in deep layers and the phenomenon of sclerosis. There is also leukocyte infiltration with localization of cells between epitheliocytes, their necrobiotic changes in the form of accumulations of granular basophilic substance. Conclusion. Based on the literature sources, it should be noted that there are only a few sources that characterize the change of the epithelium and its own plate in the course of inflammatory processes, and they are not enough to fully understand the morphological rearrangement of gums at the histological and ultrastructural levels. Special studies of mast cells and their impact on the occurrence and course of the inflammatory process in the gums have not been conducted. Until now, the question of the secretion type of tissue basophils in the course of inflammatory processes in the gums remains open

Early postoperative complications and their measures after skull base reconstruction: A study from the standpoint of plastic and reconstructive surgeons

ObjectiveIn skull base surgery, postoperative complications may be lethal and it is important to know how to deal with these. There are several reports on complications after skull base reconstruction, but it is difficult to understand which are important for plastic surgeons in charge of reconstruction. The objective of this study is to clarify the early postoperative survival-related complications after skull base reconstruction of which plastic surgeons should participate in treatment. MethodsOne hundred and seventy-seven patients who underwent skull base reconstruction at our department over the last 12 years were retrospectively surveyed. The cases of early complications in which plastic surgeons were actively involved in treatment were investigated and the preventive measures actually taken at our facility are examined in addition to treatment methods after development. ResultsPlastic surgical complications were wound infection in seven patients, impaired blood flow in transplanted tissue in two patients, cerebrospinal fluid leakage in five patients, and intracranial compression in three patients. Total number of postoperative complications were seventeen and the total complication rate was 9.6%. Complication rates tended to be higher in anterior-middle skull base cases than in anterior or middle alone cases and higher with free tissue transfer than with locoregional flap. Multivariate analysis revealed that operation time was a significantly higher risk factor (p=0.012) and preoperative chemotherapy was a significantly lower risk factor (p=0.033) for the development of complications. It was also found that the hospitalization length was significantly longer when complications occurred (p<0.0001). Wound infection was treated with removal of the cause, sufficient drainage, and irrigation. Regarding preventive measures, it is necessary to pay attention especially to intracranial contamination with epithelial components. Rapid surgical measures were necessary when blood flow of the transplanted tissue was impaired. For pedicle flaps, conservation of the feeding vessel is needed, and for free flaps, reliable vascular anastomosis is needed as preventive measures. Plastic surgeons play a role in reducing the risk of cerebrospinal fluid leakage through covering the repaired dura mater with tissue with favorable blood flow, especially in reoperation after development of leakage. Skull base reconstruction with soft tissue may cause intracranial compression, and sometimes, it is not resolved by conservative treatment and reoperation is selected. ConclusionPlastic surgical postoperative complications were clarified, and treatment methods and preventive measures for them were examined. Careful consideration of blood flow, placement, and volume of the transplanted flap is important to prevent complications.

Renal Cell Carcinoma With Fibromyomatous Stroma-The Whole Story.

Renal cell carcinoma (RCC) with fibromyomatous stroma (FMS) was included as an "emerging/provisional" entity in the 2016 World Health Organization (WHO) classification as a "RCC with (angio) leiomyomatous stroma." It has been debated whether RCCFMS represents a separate entity or a group of RCCs with overlapping morphologies. Accordingly, various names have been used to refer to the RCCs that exhibited clear cells and prominent smooth muscle and fibromatous stroma. Recent studies have demonstrated that RCCFMS indeed represents a distinct entity with subtle but distinguishable features that can be separated from other RCCs that exhibit clear cells, as well as tubulopapillary morphology and smooth muscle/fibromatous stroma, such as clear cell RCC and clear cell papillary RCC. Microscopically, the epithelial component forms tumor nodules composed of elongated and frequently branching tubules, lined by clear or mildly eosinophilic cells containing voluminous cytoplasm. Focal papillary morphology is also frequently present. Diffuse CK7 positivity is typical and is required for the diagnosis. Molecular analysis of these tumors demonstrated recurrent mutations involving the TSC/mTOR pathway. A subset of tumors with similar morphology has shown mutations involving ELOC (previously referred to as TCEB1), typically associated with monosomy 8. Finally, in addition to the more common RCCFMS that are sporadic, essentially identical tumors have been found in patients with tuberous sclerosis complex, suggesting the existence of hereditary and sporadic counterparts of this tumor. It is currently debated whether TSC/mTOR and ELOC mutated RCCFMS should be grouped together, based on their shared and overlapping morphology and common CK7 reactivity, despite the differing molecular alterations. This review outlines evidence supporting the recognition of RCCFMS as a novel subtype of RCC with morphologic, immunohistochemical, and molecular characteristics distinct from clear cell RCC and clear cell papillary RCC.

Carcinosarcoma of the stomach: four cases that expand the morphologic spectrum of gastric cancer with a primitive phenotype.

Carcinosarcoma of the stomach is a rare neoplasm characterized by the presence of both epithelial and mesenchymal malignant components. We describe four examples with a focus on the characterization of the epithelial components and the histogenetic implications for this unique tumor. All patients were men aged 40-79years. All patients developed metastatic disease, and three of them died 4-19months after the diagnosis. Sarcomatous elements included poorly differentiated spindle cell sarcoma without distinctive differentiation (n = 4), chondrosarcoma (n = 2), and rhabdomyosarcoma (n = 1). In two cases, the sarcomatous component was recognized only in metastatic lesions. Notably, carcinomatous components were characterized by multilineage and primitive cellular differentiation, including carcinoma with enteroblastic (n = 4), hepatoid (n = 3), yolk sac tumor-like (n = 1), trophoblastic (n = 1), and neuroendocrine (n = 1) differentiation, as well as conventional tubular adenocarcinoma (n = 4). On immunohistochemistry, all four cases showed varying degrees of positive expression of primitive phenotypic markers, including alpha-fetoprotein (AFP), glypican-3, or SALL4. All tumors showed mutant patterns of p53 staining, exhibiting either diffusely positive or completely negative staining. On the basis of these findings, at least some gastric carcinosarcomas are likely to be derived from carcinoma with a primitive phenotype, including AFP-producing adenocarcinoma. Our observations suggest that sarcomatous differentiation, as well as multilineage differentiation of epithelial components, may represent increased cellular plasticity of gastric carcinoma with a primitive phenotype.

Desmoplastic Small Round Cell Tumor Is an Important Mimic of High-Grade Carcinoma in Colonic Biopsy Samples

Abstract Desmoplastic small round cell tumor (DSRCT) is a rare but aggressive malignancy that usually occurs within the intra-abdominal cavities of young adult males. Most DSRCTs can be reliably diagnosed based on the presence of characteristic morphology; coexpression of epithelial, myogenic, and neural markers; and detection of the reciprocal translocation t(11;22)(p13:21) associated with the EWS::WT1 fusion. However, occasional tumors lack classic features, affect older adults, or are located outside the abdominal cavity. Mucosal biopsy samples can pose challenges when both the stromal and epithelial components are not represented. Herein, we present a case of DSRCT that simulated clinical and histologic features of a colonic adenocarcinoma. Biopsy sampling revealed nests of cytokeratin-positive epithelioid cells that simulated a high-grade carcinoma with neuroendocrine features. This case report emphasizes the importance of considering this rare entity when presented with high-grade epithelioid tumors that occur in young patients.

The histological and immunohistochemical features of a metastatic mammary carcinosarcoma in a dog - a case report

A carcinosarcoma is a tumor composed of cells morphologically resembling both malignant epithelial and mesenchymal components. An 11-year-old, female, mixed-breed terrier was referred to the clinic with complaints of anorexia, vomiting and exercise intolerance. Clinically, tumoral masses were seen in the mammary glands. During necropsy, multilobulated calcified masses were observed in several visceral organs (the liver, kidneys, lungs, small intestines, lymph nodes and thyroid) and both right and left (3rd and 4th) mammary glands. Immunohistochemically, Thyroglobulin, SMA, TTF-1, S100, CD34, and p53 were negative in both epithelial and mesenchymal areas, however, Ki-67 showed high proliferation, especially in the mesenchymal areas. While the positivity of vimentin expression was high in the mesenchymal component of the tumor, the positivity of cytokeratin (CK7 and CK19) expressions was high in the epithelial component of the tumor. In the case of a carcinosarcoma, there is a probability that not only the carcinomatous part, but also the sarcomatous part will metastasize. Despite being uncommon, canine carcinosarcomas should always be considered in the differential diagnosis of mixed mammary tumors, if they include both components. There have not been many previous studies dealing with the metastasis of a mammary carcinosarcoma in dogs as an aggressive tumor. Therefore, we consider this report a worthy contribution and have defined the multiple organ metastasis of a mammary carcinosarcoma.

Hidronefrotik fonksiyon göstermeyen böbrekli genç erkek olguda mikst epitelyal stromal tümör: Literatür bulguları ile karşılaştırma

The mixed epithelial and stromal tumor (MEST) family is comprised of adult cystic nephroma with a dominant cystic component and MEST with a dominant solid component. MEST is the rarely observed benign, biphasic tumor of the kidney with a mixed epithelial and stromal component. In the examinations of a 24-year-old male patient who presented with abdominal pain, grade-4 hydronephrosis was detected. In the microscopic examination of his nephrectomy specimen, there were tubular structures with cuboidal epithelium in different diameters within the ovarian stroma. The patient was diagnosed with MEST via morphological and immunohistochemical findings. We aimed at comparing the clinical and histopathological characteristics of our case, which we diagnosed with MEST, which is encountered in limited numbers in young men and has never been reported together with a nonfunctional kidney before, to the literature data. Keywords: Mixed epithelial and stromal tumor, nonfunctional kidney, male.

The role of spatial transcriptomic profiling to determine androgen receptor signaling and immune infiltration in prostate cancer

272 Background: Prostate cancer (PCa) in the transition zone (TZ) accounts for approximately 30% of disease and tends to present with higher PSAs with a lower risk of seminal vesicle invasion, extra-capsular extension, and risk of biochemical recurrence compared with peripheral zone (PZ) tumors. The underlying biological mechanism for these differences is poorly understood. Here, we performed spatial transcriptomic profiling to elucidate the molecular differences between TZ and PZ PCa. Methods: We identified three patients who underwent radical prostatectomy for PCa (one each with PZ only, TZ only, and both PZ and TZ tumors) and used the NanoString’s Digital Spatial Profiling (DSP) platform to quantify whole transcriptomic gene expression data (17,128 genes) in multiple regions of interest (ROI) per patient (42 cancer and 8 normal samples). Four morphology markers to facilitate ROI selection in both cancer and normal areas (SYTO13 for nucleus, PanCK for epithelium, SMA for stroma and CD45 for immune cells) were selected. Raw counts for 17,128 genes were imported to R v.4.1.0 for downstream data analyses. Counts were Q3 normalized and scaled (Z-score) to enable plotting of all genes on the same axes. Differential gene expression analysis using a linear model fit by empirical Bayes moderation, gene set enrichment analysis (GSEA) by cancer hallmarks, XCell gene sets for pathway enrichment and immune cell deconvolution using CIBERSORT was performed. Results: There were grade group (GG) 4 (n=10) and 5 (n=10) tumors in PZ and GG 3 (n=10), 4 (n=11) and 5 (n=1) cancers in TZ regions. We observed distinct gene expression profiles between PZ (n = 20) and TZ (n=22) tumors. Interestingly, androgen receptor (AR) signaling was significantly higher in TZ PCa ROIs compared to PZ ROIs in both GSEA (false discovery rate &lt; 5%) and the androgen subcomponent of the genomic prostate score (p&lt;0.001), regardless of grade, epithelial, stromal or immune component of the region. To standardize the comparison, CIBERSORT’s absolute immune signature scores were only computed for GG4 tumors and found to be significantly higher in PZ GG4 tumors compared to TZ GG4 tumors. Notably, CD4+ memory T cells were significantly higher in PZ GG4 regions compared to TZ GG4 tumor regions (p&lt;0.05). Conclusions: Here, we demonstrate distinct gene expression profiles of PZ and TZ PCa. Specifically, we observed higher AR signaling in TZ cancers and higher levels of immune infiltration on PZ cancers. This is in concordance with prior knowledge that TZ tumors may be associated with higher serum PSA and PZ tumors may be associated with inflammation. Further studies are needed to discern the biological and clinical significance of the different molecular features of PZ and TZ PCa.

Nuclear expression of pSTAT3Tyr705 and pSTAT3Ser727 in the stromal compartment of localized hormone-naïve prostate cancer

BackgroundThe signal transducer and activator of transcription 3 (STAT3) is involved in the progression of different tumors including prostate cancer (PCa). The expression of STAT3 in benign and malignant epithelium has been described previously but it has not been described in the stromal compartment. The aim of the present study was to evaluate the nuclear expression and prognostic value of different forms of phosphorylated STAT3 in the stromal compartment of non-cancer and cancer areas of prostatic tissue. Material and methodsTissue microarray cores from radical prostatectomy of 225 patients with hormone-naïve localized PCa were immunostained for two phosphorylated forms of STAT3, pSTAT3Tyr705 and pSTAT3Ser727. The prognostic value of the expression levels was studied by Cox regression analysis and biochemical recurrence (BCR)-free survival illustrated by Kaplan-Meier curves. ResultsExpression of pSTAT3Tyr705 and pSTAT3Ser727 in the stromal compartment of cancer tissue was lower compared with non-cancer areas. In univariable and multivariable Cox regression analysis, expression levels of pSTAT3Tyr705 and STAT3Ser727 showed similar prognostic value as pathological T-stage, Gleason score and surgical margin status. Kaplan–Meier survival analysis showed that low nuclear expression levels of pSTAT3Tyr705 and pSTAT3Ser727 in stromal cells in cancer compartment and in non-cancer areas were related to BCR-free survival. ConclusionsNuclear expression of pSTAT3Tyr705 and pSTAT3Ser727 in the stromal cells mirrors previous findings in the epithelial component in that it displays prognostic value in men undergoing radical prostatectomy for localized hormone-naïve PCa.

Diagnostic Dilemma During Laparoscopic Cystectomy of Twisted Serous Cystadenofibroma of Ovary in Adolescent Girl – A Case Report with Literature Review

The most ovarian tumor arises from the surface epithelium and the serous tumor is the most common histological variant. Serous cystadenofibroma is a rare variant of serous tumor that comprises both epithelial and fibrous stromal components. They are benign in nature but may often be misinterpreted as malignant nature due to their solid cystic nature with papillary projections. We herein report a case of twisted right ovarian cyst in 17 years unmarried girl that was clinically and radiologically benign and hence managed laparoscopically. Intraoperatively cyst ruptured that released clear serous fluid. During cystectomy, multiple small to large size (maximum 2x2 cm) papillary projections were noted within the uninoculated cyst without any other solid components. With the possibility of a borderline tumor, the patient party was counseled and opted for cystectomy with the possible need for a second surgery. The final histopathology report was benign serous cystadenofibroma.

Ductal papilloma with atypical ductal hyperplasia – Understanding the importance of immunohistochemistry- A case report

Solitary intraductal papilloma of the breast is a common benign mammary proliferative disease and is the most common neoplasm associated with nipple discharge in women. Women with solitary papillomas have 1.5-2.0 times increased risk of developing invasive carcinoma. The papillary lesions of the breast include a broad spectrum of disorders from benign papilloma, atypical papilloma to papillary carcinoma. Benign papilloma on core needle biopsy has been found to have concurrent malignancy in about 3–5% of cases at excision. Solid papillomas commonly pose a diagnostic dilemma due to similarities with other ominous papillary lesions. The presence of ADH within a papilloma and/or in the surrounding breast is associated with an increased risk of recurrence or invasive carcinoma. The present study undertakes to fully describe the morphological changes occurring within the epithelial component of central papillomas and to search for factors of prognostic significance concerning recurrence, progression and differentiation of atypical ductal hyperplasia.

Clinical outcomes of thyroid tumours with concurrent epithelial and mesenchymal components in 14 dogs (2006-2020).

BackgroundWhile rare, multiple individual case reports have described mixed thyroid tumours in dogs containing both epithelial and mesenchymal neoplastic components.ObjectivesIn this retrospective case series, we describe the clinical presentation, treatment and outcome of 14 dogs of canine thyroid tumours with concurrent mesenchymal and epithelial neoplastic populations.MethodsFourteen cases were retrospectively abstracted from nine institutions. Histopathologic samples and reports were collected from 10/14 dogs and reviewed by a single board‐certified anatomic pathologist.ResultsAll 14 dogs had curative‐intent surgery to remove the thyroid neoplasm. The most common surgery performed was a unilateral thyroidectomy (10/14 dogs). Postoperatively, systemic therapy was administered in eight dogs. Six dogs developed local recurrence with a median time to loco‐regional recurrence of 53 days. Ten dogs developed metastatic disease with the most common metastatic site being the lungs (6/10 dogs), with a median time to metastasis of 93 days. Ten dogs were euthanised due to locoregional or distant progression of their mixed thyroid neoplasm. The overall median survival time was 156 days (95%CI: 49–244). The median survival time for dogs treated with adjuvant therapy was 189 days (95%CI: 24–244), whereas dogs without adjuvant therapy had a median survival time of 156 days (95%CI: 35‐upper limit could not be calculated; p = 0.62).ConclusionThe thyroid tumours with both mesenchymal and epithelial components in this small sample set were associated with a poor prognosis after surgical excision with or without adjunctive therapy.

HER2 Overexpression and Amplification in Uterine Carcinosarcomas With Serous Morphology.

Uterine carcinosarcoma (UCS) is an aggressive malignancy with few treatment options. A recent clinical trial has shown an increase in progression-free survival in patients with human epidermal growth factor receptor 2 (HER2)-positive serous endometrial carcinomas treated with anti-HER2-targeted therapies. Few studies have evaluated HER2 expression/amplification in UCS. Similar to serous endometrial carcinoma, the majority of UCS have TP53 mutations and a serous epithelial component, suggesting that UCS may show similar rates of HER2 positivity and therapeutic response. Therefore, we evaluated HER2 expression/amplification in a cohort of UCS over a 5-year period. HER2 immunohistochemistry (IHC) and chromogenic in situ hybridization were performed on tissue microarray and whole tissue sections and scored according to the most recent clinical trial recommendations. Three of 48 UCS (6%) had strong (3+) HER2 IHC expression, and 3 cases (6%) were equivocal (2+). Seven cases (15%) had HER2 amplification by chromogenic in situ hybridization, including all 3 with overexpression and 2 that were equivocal by IHC. Mismatch repair (MMR) protein, p53, and programmed cell death-ligand 1 (PD-L1) expression status was obtained from prior whole section analyses. All HER2-positive cases had a serous morphology and aberrant p53 expression. Only minimal PD-L1 expression was seen in the HER2-positive cases, and none had MMR loss. A subset of UCS with serous morphology have overexpression and/or amplification of HER2, which may predict response to HER2-targeted therapies. HER2-positive UCS may be less susceptible to immune checkpoint inhibition as they uncommonly show MMR deficiency and/or strong PD-L1 expression. Thus, HER2-targeted therapies could be of clinical utility in a subset of UCS without other adjuvant treatment options.

Studying the role of mesenchymal compartment during human iPSC differentiation into bronchial epithelium

Chronic airway diseases are a common medical condition worldwide and include diseases such as cystic fibrosis, asthma or chronic obstructive pulmonary disease (COPD). COPD is the third leading cause of death in the world, and there is still no curative treatment. Air liquid interface cultures (ALI) mimic the lung development and disease. We and others have recently generated a functional airway multiciliated epithelium in ALI conditions by using human pluripotent stem cells, called “iALI” (Ahmed et al., BioRxiv, 2020). During this differentiation process, a mesenchymal stromal component is consistently described but poorly studied. To comprehensively define the cell types, mechanisms driving iALI model and understand the crosstalk between epithelial and mesenchymal components, we performed single-cell mRNA sequencing. RT-qPCR and immunofluorescence assays were used to confirm the sequencing results. In addition to the epithelial cell subtypes, the iALI cultures also contain a previously poorly documented EPCAM-COL1A1 + DCN+ mesenchymal stromal compartment. Several populations, that partially overlap can be identified : 1/ACTA2+ myofibroblasts including fibromyocytes characterized by high expression of contractile genes such as CNN1 and TAGLN, 2/a transition population closer to epithelial cells expressing MAF and the long non coding mRNA EPB41L4A-AS1 and 3/a highly proliferating PCNA + CDK1+ cells. Moreover, stromal cells expressed growth factors such as FGF10 while its receptor FGFR2 is expressed on the epithelial cells, suggesting that stromal cells could support iALI development. These data provide high-resolution insights into the complexity and plasticity of the iALI and suggest that a crosstalk between epithelium and mesenchyme is essential to iALI development. The functional role of the relevant pathways will be assessed in our iALI model in control condition but also in a pathological context.

Kidney-Targeted Renalase Agonist Prevents Cisplatin-Induced Chronic Kidney Disease by Inhibiting Regulated Necrosis and Inflammation.

Repeated administration of cisplatin causes CKD. In previous studies, we reported that the kidney-secreted survival protein renalase (RNLS) and an agonist peptide protected mice from cisplatin-induced AKI. To investigate whether kidney-targeted delivery of RNLS might prevent cisplatin-induced CKD in a mouse model, we achieved specific delivery of a RNLS agonist peptide (RP81) to the renal proximal tubule by encapsulating the peptide in mesoscale nanoparticles (MNPs). We used genetic deletion of RNLS, single-cell RNA sequencing analysis, and Western blotting to determine efficacy and to explore underlying mechanisms. We also measured plasma RNLS in patients with advanced head and neck squamous cell carcinoma receiving their first dose of cisplatin chemotherapy. In mice with CKD induced by cisplatin, we observed an approximate 60% reduction of kidney RNLS; genetic deletion of RNLS was associated with significantly more severe cisplatin-induced CKD. In this severe model of cisplatin-induced CKD, systemic administration of MNP-encapsulated RP81 (RP81-MNP) significantly reduced CKD as assessed by plasma creatinine and histology. It also decreased inflammatory cytokines in plasma and inhibited regulated necrosis in kidney. Single-cell RNA sequencing analyses revealed that RP81-MNP preserved epithelial components of the nephron and the vasculature and suppressed inflammatory macrophages and myofibroblasts. In patients receiving their first dose of cisplatin chemotherapy, plasma RNLS levels trended lower at day 14 post-treatment. Kidney-targeted delivery of RNLS agonist RP81-MNP protects against cisplatin-induced CKD by decreasing cell death and improving the viability of the renal proximal tubule. These findings suggest that such an approach might mitigate the development of CKD in patients receiving cisplatin cancer chemotherapy.

An Integrated Epigenomic and Genomic View on Phyllodes and Phyllodes-like Breast Tumors.

Simple SummaryFibroepithelial tumors of the breast represent a spectrum of mostly benign diseases. However, some of these tumors tend to recur and may even spread distantly to other body sites. Prediction of their biological behavior is currently morphology-centered. In this study, we set out to answer the question of whether their biologic behavior might be reflected by specific DNA methylation and copy number profiles, both of which can be determined alongside each other in a diagnostic routine workflow through microarrays. We discovered that the fibroepithelial tumors seem to fall into two distinct copy number variant patterns and that they are epigenetically related. Our study underlines the diagnostic usefulness of combined methylation/copy number profiling in fibroepithelial breast tumors to predict clinical outcomes.Fibroepithelial lesions (FL) of the breast, in particular, phyllodes tumors (PT) and fibroadenomas, pose a significant diagnostic challenge. There are no generally accepted criteria that distinguish benign, borderline, malignant PT and fibroadenomas. Combined genome-wide DNA methylation and copy number variant (CNV) profiling is an emerging strategy to classify tumors. We compiled a series of patient-derived archival biopsy specimens reflecting the FL spectrum and histological mimickers including clinical follow-up data. DNA methylation and CNVs were determined by well-established microarrays. Comparison of the patterns with a pan-cancer dataset assembled from public resources including “The Cancer Genome Atlas” (TCGA) and “Gene Expression Omnibus” (GEO) suggests that FLs form a methylation class distinct from both control breast tissue as well as common breast cancers. Complex CNVs were enriched in clinically aggressive FLs. Subsequent fluorescence in situ hybridization (FISH) analysis detected respective aberrations in the neoplastic mesenchymal component of FLs only, confirming that the epithelial component is non-neoplastic. Of note, our approach could lead to the elimination of the diagnostically problematic category of borderline PT and allow for optimized prognostic patient stratification. Furthermore, the identified recurrent genomic aberrations such as 1q gains (including MDM4), CDKN2a/b deletions, and EGFR amplifications may inform therapeutic decision-making.

Diagnostics for Dermatologic Diseases with Autoantibodies.

Dermatologic diseases with autoantibodies were recognized early as autoimmunity became accepted as a pathogenic immunologic concept. Laboratory testing to identify disease-defining autoantibodies and investigate their role in pathophysiology has evolved since. Blistering dermatologic diseases, profiled by autoantibody production, target epithelial components critical in cell-cell and cell-matrix adhesion, resulting in epithelial separation and other characteristic features of the disorders. This review covers the clinical indications for dermatologic disease-related autoantibody testing, the specifics of procuring specimens to test, the available diagnostic tests, and information provided by the testing. Atypical, uncharacteristic, and less well-known clinical and autoantibody profiles as well as several of the many future prospects for expansion of the testing applications are elaborated on in the online Data Supplement. Autoantibody-associated dermatologic diseases are acquired immunologic disorders that have considerable clinical implications affecting essential barrier functions of skin and mucous membranes and causing discomfort, including pain and pruritus. Certain of the diseases can have life-threatening manifestations, and treatments can have significant side-effects. The skin diseases may presage other clinical associations that are important to recognize and treat. Laboratory testing aids in the diagnosis of these diseases through identification of the autoantibodies and is essential for prompt and precise knowledge of the disease type for prognosis, further clinical evaluations, and treatment decisions.